Biodegradable high-molecular polymers can be used, for example, as bases for such pharmaceutical preparations as microcapsules. U.S. Pat. No. 4,683,288, for instance, describes that polycondensation of lactic acid and/or glycolic acid in the presence or absence of a catalyst gives polymers or copolymers of these as biodegradable high-molecular polymers.
U.S. Pat. No. 4,767,628 discloses a method of producing sustained release microcapsules in which such biodegradable high-molecular polymers are used. Furthermore, U.S. Pat. No. 4,728,721 describes that the initial release of a drug from microcapsules can be decreased by removing readily water-soluble low-molecular compounds from biodegradable high-molecular polymer solutions by washing with water.
Sustained-release preparations produced by dispersing a drug in a biodegradable high-molecular polymer should desirably be capable of releasing the drug at a voluntarily controlled rate. Generally, the drug release period of a sustained-release preparation is adjusted by the molecular weight of the biodegradable high-molecular polymer, which serves as the base for said preparation. In most cases, however, the initial drug release is too great although said release may vary depending on the kind and amount of the polymer.
The removal of readily water-soluble low-molecular compounds by the above-mentioned method of U.S. Pat. No. 4,728,721 indeed results in an improved initial release. The extent of improvement, however, is such that it is impossible to suppress only the initial release and thereby increase the rate of release in later stages although it is possible to maintain the rate of drug release at a nearly constant level throughout the whole release period.
As a result of intensive investigations made in an attempt to solve the above problems, it was found that a relatively low-molecular fraction of the biodegradable high-molecular polymer is deeply involved in the initial release.
Thus, it was found that the high-molecular polymer produced by the polymerization reaction (cf. U.S. Pat. Nos. 4,683,288 and 4,728,721) contains a large amount of oligomers with a molecular weight of 1,000 or less as well as the starting monomer or monomers. It was revealed that such a relatively low-molecular fraction causes an excess initial release from preparations in which said high-molecular polymer is used as the wall substance.
Ordinary purification methods such as washing with water cannot eliminate the relatively low-molecular fraction (oligomers) mentioned above from the high-molecular polymer. As a result of intensive investigations, the present inventors found a method which enables the removal of said fraction and have now completed the present invention.